Evaluation of teniposide (VM-26)-induced toxicity on mouse spermatogenesis by flow cytometry

Alteration in the testicular weight and various germ cell populations was studied in male mice treated with different doses (0.05, 0.25, 0.5, 1.0 and 2.0 mg/kg b. wt.) of teniposide (VM-26) at various post-treatment time periods. Treatment of mice with different doses of teniposide did not significantly alter the testicular weights, irrespective of the drug dose used. Flow-cytometric analysis of germ cells of the untreated control mice testes revealed four distinct DNA peaks corresponding to elongated spermatids (HC), round spermatids (1C), spermatogonia and non-germ cells (2C) and primary spermatocytes (4C). The region between 2C and 4C peaks represents cells that are actively synthesizing DNA (S-phase cells). Treatment of mice with different doses of teniposide resulted in a significant depletion in the relative percentage of spermatogonia from day 2 to 35 post-treatment depending on the drug dose. DNA-synthesizing, i.e. S-phase, cells declined significantly at day 1 post-treatment and continued to decline up to day 70 post-treatment for all the drug doses studied, except 2 mg/kg drug dose at day 28 post-treatment. A significant decline in the relative percentage of primary spermatocytes (4C) was observed at day 7 that continued up to day 70 post-treatment depending on the drug dose. Round spermatids (1C) declined significantly at day 21 post-treatment after administration of 0.25--2.0 mg/kg VM-26. The relative percentage of elongated spermatids showed a significant decline at day 28 after 1 and 2 mg/kg drug treatment. These alterations in different germ-cell populations are reflected in the various germ-cell ratios. The 4C:2C ratio showed a significant decline at day 7 and 14 post-treatment after 1 and 2 mg/kg VM-26 treatment, while the 1C:2C ratio declined significantly at day 21 post-treatment in the mice treated with 0.5 and 2.0 mg/kg of VM-26. 4C:S-phase and 1C:4C ratios increased significantly from day 1 to 70 post-treatment, depending on the drug dose. Our study demonstrates that the treatment of mice with low doses of VM-26 exerts cytotoxic effects on various germ-cell populations.     

Influence of teniposide (VM-26) on radiation-induced damage to mouse spermatogenesis: a flow cytometric evaluation

The effect of teniposide (VM-26) 0.05 mg/kg body weight treatment on spermatogenesis of mice exposed to 0, 0.5, 1, 2, and 3 Gy gamma-radiation was evaluated flow cytometrically. Whole body irradiation with 1 to 3 Gy resulted in a significant decline in testis weight from Day 14 to 35 post-irradiation depending on the exposure dose. Treatment of mice with teniposide before irradiation advanced the decline in testicular weight by several days, especially at 3 Gy, where a significant decline in testicular weight was observed at Day 7 post-irradiation when compared with the double distilled water (DDW)+irradiation group. The relative percentage of the 2C population declined significantly in the VM-26+irradiation group in comparison with the DDW+irradiation group at various post-irradiation time periods depending on the exposure dose. A significant depletion in the relative percentage of S-phase cells was observed as early as Day 1 post-irradiation in the VM-26+irradiation group when compared with the DDW+irradiation group after exposure to 1 to 3 Gy. This decline continued up to Day 21 post-irradiation after exposure to 2 Gy. The relative percentage of primary spermatocytes showed a consistent decline after exposure to various doses of gamma-radiation in the VM-26+irradiation group when compared with the DDW+irradiation group at different time periods, with a few exceptions, especially at higher doses. The pattern of decline in the relative percentage of round spermatids was similar to that of primary spermatocytes, where a significant decline was observed at various post-irradiation time periods in the VM-26+irradiation group in comparison with the DDW+irradiation group. These changes in the relative germ cell percentages are manifested as alterations in the ratios of various germ cell populations. The 4C:2C ratio declined consistently from Day 1 to Day 70 post-irradiation in the VM-26+irradiation group at all exposure doses. Similarly, the 4C:S-phase ratio in the VM-26+irradiation group also showed a significant decline at different post-irradiation time periods when compared with the DDW+irradiation group depending on the exposure dose. The reduction observed in the relative percentages of various cell populations was higher in the combination group when compared with the DDW+irradiation controls, indicating potentiation of damage to male germ cells by teniposide treatment before irradiation.     

Acute Spermatogenic Effects of Bromoacetic Acids

Chlorine and bromine can react with natural organic substancesin source waters to form haloacetic acids, major disinfectionby-products of water chlorination. Several toxic effects includingtesticular damage have been attributed to the chloroacetic acidsbut little information is available on the bromine analogues.In this report we present the results of acute toxicity andacute spermatotoxicity studies of monobromoacetic acid (MBAA)and dibromoacetic acid (DBAA). In adult male rats the acuteoral toxicity of MBAA was 10-fold that of DBAA (LD50 177 vs1737 mg/kg). No reproductive-related endpoints were affectedin rats given a single dose of 100 mg MBAA/kg or 14 daily dosesof 25 mg MBAA/kg/day. In rats dosed with DBAA, serum testosteronefell to 17% of control 2 days after a single dose of 1250 mg/kgbut returned to control levels by Day 14. Marked effects onsperm motion were seen on post-treatment Days 14 and 28. Degenerativeflagellar changes in cauda sperm were present on Day 14 whileabnormal sperm head shapes and flagellar degeneration were observedin both caput and cauda sperm on Day 28. Histopathology indicatedaltered spermiation at all timepoints as evidenced by retentionof Step 19 spermatids beyond Stage VIII of the cycle of theseminiferous epithelium. Disorganization, distortion, and degenerationof late spermatids were also observed. On Day 14 structuresresembling residual bodies were rarely seen in the testis butwere numerous in the epididymis. Caput sperm counts were decreased on Day 2 and cauda sperm counts were decreased on Days14 and 28. The data indicate that DBAA is a testicular toxicantin the rat with late and elongating spermatids being particularlysusceptible germinal cells.     

Toxicity of intraperitoneally administered antitumour drugs in athymic rats

The toxicity of eight anticancer drugs given intraperitoneally to athymic rats was investigated to define the maximum tolerable doses (MTD). Drugs were given once weekly. Toxicity was assessed as percentage loss of body weight (LBW%) or percentage toxic death rate (TDR%) during the first week after drug administration. LBW% and TDR% were significantly correlated, r = 0.58 p less than 0.00001. From the regression equation for the relationship between LBW% and TDR%, 10 percent TDR (LD10), usually regarded as equivalent to MTD in animals, was found to correspond to 14 percent LBW. From the individual regression equations for LBW% and dose for each of six drugs, MTDs were calculated to be as follows; doxorubicin 7 mg/kg, cyclophosphamide 100 mg/kg, mitomycin C 1.8 mg/kg, cisplatin 8 mg/kg, vindesine 0.8 mg/kg and vincristine 0.9 mg/kg. LD10 was found to be 40 mg/kg for both carmustine (BCNU) and etoposide.     

Effect of acute exposure to boric acid on the male reproductive system of the rat

Adult male rats were dosed orally on d 0 with 0 or 2000 mg/kg of boric acid and killed on posttreatment d 2, 14, 28, and 57, or dosed with 0, 250, 500, 1000, or 2000 mg/kg of boric acid and killed on posttreatment d 14. At d 14, atypical structures that appeared to be enlarged irregular cytoplasmic lobes of Step 19 spermatids were observed in Stage VIII seminiferous tubules of rats dosed with 1000 and 2000 mg/kg. Abnormal retention of Step 19 spermatids and residual bodies was also observed in Stage IX-XIII tubules of these rats. The retained spermatids and residual bodies were seen in both the luminal and basal regions of the epithelium. A substantial increase in the testicular sperm head count occurred in animals dosed with 2000 mg/kg. Abnormal caput epididymal sperm morphology and reduced caput epididymal sperm reserves were observed at 1000 mg/kg and higher. Serum LH, FSH, TSH, and prolactin values were not affected at any dosage. At d 28, rats dosed with 2000 mg/kg exhibited continued retention of Step 19 spermatids into Stage X, abnormal caput and cauda sperm morphology, and decreased percentages of motile cauda spermatozoa with reduced straight-line swimming velocities. By d 57 substantial recovery was apparent; some retention of Step 19 spermatids into Stage X tubules was still present in two out of six rats but the sperm parameters were comparable to controls. The study indicated that acute oral exposure to boric acid adversely affected spermiation and sperm quality in the adult male rat. At the dosages used the effects appeared reversible. The no-effect level was 500 mg/kg.     

Effect of vitamins C and E on spermatogenesis in mice exposed to cadmium

Cadmium (Cd) is a potential pollutant of the environment. It manifests cyto-toxic effects in different organs in animals. In the present study, intraperitoneal injection of CdCl(2) (1mg/kg body weight) increased lipid peroxidation in Swiss mice testes indicating oxidative stress during 5th to 8th week of post-treatment .The enzymatic activity of superoxide dismutase (SOD), catalase (CT) and peroxidase (PD) were significantly decreased over the post-treatment phase in Cd-treated mice testes compared to vehicle controls. Further, ascorbic acid content also declined significantly in Cd-exposed mice testes. Following Cd treatment, a marked increase in sperm abnormality percentage and significant decrease in sperm count was observed. The purpose of the present study was to evaluate the effect of vitamins C and E supplementation on Cd-treated mice testes. Therefore, Cd-treated mice groups were injected with vitamins C and E, separately, to assess the effect of the vitamins in combating Cd-induced cytotoxicity and other manifestations. Supplementation of vitamin C (10mg/kg body weight) and vitamin E (100mg/kg body weight) to Cd-induced mice groups declined lipid peroxidation, increased sperm count profile, depressed the percentage of sperm abnormality, increased the activity of antioxidant enzymes mentioned above and also increased the concentration of ascorbic acid to a measurable extent. The role of vitamins in reducing oxidative stress-related effects on spermatogenesis in Cd-treated Swiss mice testes have been reported.     

Differential up-regulation of striatal dopamine transporter and alpha-synuclein by the pyrethroid insecticide permethrin

The effects of permethrin on striatal dopaminergic biomarkers were assessed in this study. Retired breeder male C57 B1/6 mice were given an ip dose of permethrin (0.1-200 mg/kg) at 7-day intervals, over a 2-week period (Days 0, 7, and 14). Animals were then sacrificed 1 day (t = 1), 14 days (t = 14), or 28 days after the last treatment (t = 28). Dopamine transporter (DAT) protein as assayed by Western blotting was increased to 115% in the 0.8 mg/kg group over that of control mice at t = 1 (P < 0.05). At t = 14, this value increased to 140% of control, and declined slightly to 133% of control at t = 28. The mice given the 1.5 mg/kg dose displayed a significant increase in DAT protein only at t = 28, to 145% of controls. Thus, upregulation of the DAT at low doses of PM is variable 24 h after treatment, and seems to stabilize by t = 28. The threshold dose for increasing DAT expression in Western blots by t = 28 was 0.2 mg/kg permethrin. [(3)H]GBR 12935, used to assay DAT binding, followed the same trend as that for the Western blotting data for 0.8 and 1.5 mg/kg doses of permethrin over the 4 weeks posttreatment. At 200 mg/kg permethrin, DAT protein was unchanged vs controls (t = 1), but had significantly increased by t = 14 and continued to increase at t = 28, suggesting that the reduced dopamine transport at this dose was due to nerve terminal stress and that recovery had occurred. The protein alpha-synuclein was also significantly induced at the 1.5 mg/kg dose at t = 1; however, unlike DAT up-regulation, this effect had declined to control values by t = 14. Maximal induction of alpha-synuclein protein occurred at a dose of 50 mg/kg permethrin. These data provide evidence that the pyrethroid class of insecticides can modulate the dopaminergic system at low doses, in a persistent manner, which may render neurons more vulnerable to toxicant injury.     

Determination of the proximate teratogen of the mouse fetal alcohol syndrome: 1. Teratogenicity of ethanol and acetaldehyde

The proximate teratogen of the fetal alcohol syndrome is unknown. CD-1 mice were treated ip on Day 10 of gestation with 2, 4, 6, or 7 g/kg ethanol. The percentage of resorptions and malformed fetuses was increased and mean fetal weight was decreased in a dose-related manner. Treatment with 7 g/kg ethanol ip on one of gestational Days 7, 8, 9, 10, or 11 significantly increased the percentage of malformed fetuses and decreased fetal weight. In addition, treatment on Days 10 or 11 significantly increased the percentage of resorptions. Coadministration of 100 mg/kg of 4-methylpyrazole, an inhibitor of alcohol dehydrogenase, orally with 6 g/kg ethanol ip on Day 10 of gestation dramatically increased the embryotoxicity of ethanol. Five ip treatments of 200 mg/kg acetaldehyde at 2-hr intervals on Day 10 of gestation did not significantly increase the percentage of resorptions and malformed fetuses or decrease fetal weight. These data suggest that ethanol is the proximate teratogen of the fetal alcohol syndrome in CD-1 mice.     

Increased permeability of the rat biliary tree by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treatment and protection by hepatoactive agents

Male Sprague-Dawley rats were treated ip on Day 0 with 0, 20, 50, or 100 micrograms/kg of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and biliary tree permeability was evaluated on Days 2, 4, 7, 10, 14, or 20 by segmented retrograde intrabiliary injection of [3H]sucrose or [14C]mannitol. Seven days after 100 micrograms/kg TCDD, the percentage recovery in bile of both [3H]sucrose (73.9 +/- 4.2 vs 27.6 +/- 7.6, control vs TCDD, means +/- SE) and [14C]mannitol (22.7 +/- 2.2 vs 12.1 +/- 2.2) was decreased, demonstrating that the permeabilities of both the intracellular (canalicular) and paracellular pathways were increased. Seven days after 50 micrograms/kg TCDD, the recovery of [3H]sucrose was decreased (73.5 +/- 5.4 vs 39.0 +/- 2.8) but the recovery of [14C]mannitol was not (25.5 +/- 1.5 vs 22.9 +/- 1.9). Thus, an increase in paracellular permeability is obtained at a lower dose of TCDD. In rats treated with 100 micrograms/kg TCDD on Day 0, co-treatment with chlordecone (15 mg/kg/day on Days 2-6) or thyroxine (50 micrograms/kg on Day 2) had no effect. Pregnenolone-16 alpha-carbonitrile (75 mg/kg/day on Days 4-6) treatment increased [14C]mannitol recovery in both TCDD and control groups; its effect must not be specific. Methimazole given in drinking water (0.5%) on Days -7 through 7 reversed the increased permeability effects of TCDD (100 micrograms/kg) without affecting the biliary tree permeability ([14C]mannitol recovery) of control animals.     

Absorption, distribution and excretion of 14C-pilocarpine following oral administration to rats

The absorption, distribution and excretion of pilocarpine (CAS 92-13-7) were studied after single oral doses of 14C-pilocarpine hydrochloride (CAS 54-71-7) to the Sprague-Dawley rat, administered in aqueous solution mainly at a dose level of 0.3 mg/kg. Rats also received single intravenous doses at 0.3 mg/kg so as to compare 14C pharmacokinetics and excretion. The oral 14C-dose was rapidly and almost completely absorbed from the duodenum and small intestine within 30 min in the male rat and 14C concentrations in plasma declined biexponentially with a terminal half-life of about 9 h. Over the oral dosage range studied, i.e. 0.1-1.0 mg/kg, there was no evidence of significant non-proportionality for Cmax of 14C, whereas there was some such evidence for AUG24. Tissue 14C concentrations in male and pregnant female (Day 18) rats peaked at 0.5 h and mostly declined in parallel with those in the plasma. Excluding tissues concerned with drug absorption and elimination, 14C concentrations in most tissues were similar to, or lower than, those in the plasma. The extent of placental transfer of 14C was small and less than 0.09% of a maternal dose reached a foetus. 14C diffused into maternal milk at concentrations similar to those in the plasma. The 14C-dose was rapidly excreted in male rats, mostly in the urine (about 80%) during 6 h post dose. Recoveries of 14C in mass balance (excretion) studies were in the range 96-100%. There were no apparent gender differences in the disposition of 14C-pilocarpine in the rat.     

Time dependent effects produced in chicks after prenatal injection of methylmercury

Methylmercury dicyandiamide (0.05 to 10 mg/kg egg) injected into the yolk sac of fertilized chicken eggs prior to incubation produced a dose related decrease in the percentage of chicks hatched (90-57% of control). With dosage fixed at 0.5 or 5.0 mg/kg egg and injections made on Days 0, 7 or 14 of incubation, hatches were 90, 68 and 75%, respectively, for the low dose and 63, 13 and 18% for the high dose. In contrast to results obtained from chicks hatched from eggs injected on Day 0 of incubation, chicks hatched from eggs injected with 0.5 or 5.0 mg MMD/kg on Day 7 or 14 were not different from controls in a detour learning situation. Administration of 14-C methylmercury revealed maximal brain radiolabel in embryos injected on Day 0 to be 10% that seen with eggs injected on Day 7 but twice that seen with eggs injected on Day 14. We tentatively conclude that a period of maximal sensitivity to the behavior effects exists prior to Day 7 and that the mechanisms of embryolethality is different from that producing the functional deficits.     

Interaction between enrofloxacin and monensin in broiler chickens

Enrofloxacin, a fluoroquinolone, and its interaction with monensin, an ionophore drug, was studied to explore the influence of enrofloxacin on drug metabolizing enzymes that can lead to physiological and toxicological consequences upon coadministration with monensin in broiler chickens. Group I, treated with 100 mg monesin/kg feed from 1 d old to 41st d of age, did not show any influence on aniline hydroxylase and cytochrome b5 levels. Group II, treated with 10 mg enrofloxacin/kg body weight per os for three consecutive days on 33rd, 34th, 35th d of age, had a highly significant decrease in aniline hydroxylase on 38th d (ie on 3rd d post-treatment with enrofloxacin); a reversal effect was noticed on the 41st day (ie on 6th d post-treatment with enrofloxacin). There was no alteration in cytochrome b5 level. Group III with monensin and enrofloxacin coadministration 100 mg monensin/kg feed from 1 d old to the 41st day + 10 mg enrofloxacin/kg body weight, per os for 3 consecutive days on the 33rd, 34th, 35th d of age) had a significant decrease in aniline hydroxylase level on the 3rd d post-treatment with enrofloxacin, but an elevation tending to reach normal on the 6th d post-treatment with enrofloxacin. Monensin + enrofloxacin coadministration did not produce any alteration in cytochrome b5 level. Creatine kinase (CK) and alanine amino transferase (ALT) levels significantly increased on the 3rd d post-treatment with enrofloxacin, but on the 6th d post-treatment with enrofloxacin the increase declined. Aspartate amino transferase (AST) significantly increased on the 6th d post enrofloxacin treatment. This study demonstrated the reversible competitive type of inhibition of enrofloxacin on CYP450 enzymes, and with coadministration with monensin produced increased CK, AST and ALT serum enzymes suggesting heart and liver injury. Simultaneous administration of enrofloxacin and monensin even at recommended levels could result in adverse interactions.     

Preclinical evaluation in monkeys of a ribavirin regimen proposed for use in Lassa fever patients

The nucleoside, ribavirin (1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamide), effective against high hazard viruses such as Lassa fever, may produce hematological changes in some species. This study determined the extent of these changes in monkeys given a schedule of ribavirin treatment similar to that used in Lassa fever-infected patients. Drug was administered iv in a 33 mg/kg loading dose, followed by 17 mg/kg every 6 hr for 4 days, then 8 mg/kg every 8 hr for an additional 6 days; control monkeys received an equivalent volume of saline. Red blood cell counts decreased significantly by Day 6 but returned to pretreatment levels by the third week post-treatment. Hematocrits were reduced 30% by Day 7, reached their nadir on Day 11 with a mean value of 22%. Hemoglobin values dropped to 7–8 mg/dl, remained at that level for 10 days, and gradually returned to pretreatment levels. Three days after discontinuance of drug, reticulocytes increased then returned to control levels by Day 44. Platelet levels increased during treatment, peaked on Day 14, and then returned to baseline values. No significant changes were observed in total and differential WBC counts. Haptoglobin, SGOT, SGPT, total and direct bilirubin, BUN, blood glucose, and body weight were not altered. These data indicate that the proposed therapeutic regimen of ribavirin modifies the normal hemogram of rhesus monkeys. Observed effects appear to be fully reversible with hemograms returning to normal limits upon discontinuance of ribavirin. This effect is an important consideration in the treatment of Lassa fever in man.     

Effects of CpG-DNA from Escherichia coli on digoxin pharmacokinetics

Deoxyribonucleic acid (DNA) from bacteria or viruses has been reported as one of the pathogen-associated molecular patterns (PAMPs) and a substance that can induce endotoxemia-like inflammation in animals. However, there has been no report on digoxin pharmacokinetics in the inflammation induced by bacterial DNA containing unmethylated CpG motifs (CpG-DNA). In this study, we investigated the effects of CpG-DNA on digoxin pharmacokinetics. We determined the degree of lipopolysaccharide contamination in CpG-DNA solution and examined the changes in digoxin pharmacokinetics in rats after CpG-DNA administration. In addition, plasma concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and nitrite/nitrate (NOx) were determined after CpG-DNA administration (5 mg/kg, i.p.). The AUC0-24 of digoxin increased significantly on Day 1-3 and CL/F decreased on Day 1 and Day 2 after CpG-DNA administration. On Day 7 after CpG-DNA administration, there were no significant differences in AUC0-24 and CL/F compared with the control group (without CpG-DNA administration). However, Kel remained relatively unchanged throughout the experiment. Plasma TNF-alpha concentrations were significantly increased at 1 h and plasma IL-1beta concentrations were significantly decreased at 6 h after administration of CpG-DNA, while plasma NOx concentrations were significantly increased at 12 h after CpG-DNA administration, compared with the control group. These findings suggest that CpG-DNA (5 mg/kg) induces a transient inflammatory condition, and that AUC0-24 and CL/F of digoxin were altered after CpG-DNA administration. Digoxin pharmacokinetics recovered within 7 d after CpG-DNA exposure.     

Age-related changes in the disposition of benzyl acetate. A model compound for glycine conjugation

The in vivo metabolism and excretion of benzyl acetate (BA), a model compound for glycine conjugation, was examined in male Fischer 344 rats and C57BL/6N mice. Rats aged 3-4, 9, and 25 months received a single oral dose of either 5 or 500 mg/kg 14C-BA, while male mice aged 2, 13, and 25 months received a single oral dose of 10 mg/kg 14C-BA. Urine and feces were collected for 96 hr. Biliary excretion and plasma elimination were also examined in male Fischer rats after iv administration of 5 mg/kg 14C-BA. In both young and old rats and mice, hippuric acid (HA) was the major urinary metabolite after oral dosing of BA. No significant age-related difference was observed in rats in the urinary elimination of BA-derived radioactivity or in the percentage of the total dose excreted as hippuric acid (approximately 95%). Twenty-five-month old rats excreted a significantly higher percentage of the total dose as benzyl mercapturic acid (approximately 2%) than did 3- to 4-month-old rats (approximately 1%) at the 5 mg dose. Benzyl mercapturic acid excretion in 3- to 4-month-old rats was also increased significantly at 500 mg/kg BA vs. 5 mg/kg BA. Fecal excretion of BA-derived radioactivity declined significantly in 25-month-old rats at both the 5 and 500 mg dose. This decrease was reflected by an age-related decline in biliary excretion and higher plasma levels of BA-derived radioactivity. Examination of plasma metabolites revealed a significantly higher level of HA and benzoyl glucuronide in 25-month rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolism and excretion of 2,4-dinitrotoluene in male and female Fischer 344 rats after different doses

Female Fischer 344 rats are less susceptible to the hepatocarcinogenic effects of 2,4-dinitrotoluene (2,4-DNT) than males. This study is a comparison of the metabolism and excretion of 2,4-DNT in male and female rats after oral doses of 10, 35, or 100 mg of 14C-2,4-DNT per kg. The major route of elimination of 14C after all doses was the urine. 4-(N-Acetyl)amino-2-nitrobenzoic acid (4Ac2NBAcid), 2,4-dinitrobenzoic acid (2,4-DNMBAcid), 2-amino-4-nitrobenzoic acid (2A4NBAcid), and 2,4-dinitrobenzyl alcohol glucuronide (2,4-DNBAlcG) were identified in urine of rats. These four compounds accounted for greater than 85% of the radioactivity excreted in urine. Female rats excreted a significantly greater percentage of the dose in the urine as 2,4-DNBAlcG at doses of 10 or 35 mg/kg when compared to males. Both sexes showed dose-dependent changes in urinary excretion of 2,4-DNT metabolites. Males excreted a smaller percentage of the dose as 2,4-DNBAcid at 100 mg/kg than at 10 or 35 mg/kg. Females excreted less of the dose as 2,4-DNBAcid and 2,4-DNBAlcG at 100 mg/kg than at 10 or 35 mg/kg. The only sex difference in 2,4-DNT metabolism or excretion of sufficient magnitude to account for the sex difference in susceptibility to the hepatocarcinogenic effects of 2,4-DNT was the greater percentage of 2,4-DNT excreted as 2,4-DNBAlcG by female rats at 10 or 35 mg/kg.     

Role of vitamin C on lead acetate induced spermatogenesis in swiss mice

In the present study significantly increased lipid peroxidation value (LPP) after a single intraperitioneal injection of lead acetate (LA) (100 mg/kg b.w.) indicated enormous generation of Reactive Oxygen Species (ROS). Lead-induced ROS has a direct inhibitory effect on the growth and differentiation of the spermatogonial cells showing a significant decline in sperm count. Chromosomal analysis of the primary spermatocytes at week 4 post-treatment in lead-treated mice revealed significantly higher no of aberrant cells including chromosomal deficiency, autosomal and XY-asynapsis plates compared to untreated control mice, Sperm morphology studies at week 1-4 and at week 8 post-treatment, indicated higher percentage of deformed sperm population compared to vehicle injected groups of mice. Supplementation of vitamin C (Vit C) at a dose of 10 mg/kg body weight to lead-treated mice groups, however, significantly reduced the LPP with a concomitant increase in sperm count, marked decrease in the no of aberrant cells and significant decline in the percentage of morphologically abnormal sperm population. Protective role of Vit C in combating lead-induced oxidative stress in mice testicular cells, has been discussed.     

Delta-9-tetrahydrocannabinol during pregnancy in the rat: effects on development of RNA, DNA, and protein in offspring brain

Either 15 or 50 mg/kg of delta-9-tetrahydrocannabinol (THC) was administered from Day 2 through Day 22 of gestation. Pair-fed and nontreated groups served as controls and all treated and control litters were fostered at birth to untreated dams. To determine the effects of THC on offspring brain development, DNA, RNA and protein values were determined at 7, 14, and 21 days of postnatal age. DNA and RNA levels appeared unaffected by THC but brain protein levels of the 50 mg/kg offspring were significantly lower than in the other groups at Day 7 and 14. This suggests that the high THC dose inhibited protein synthesis for at least the first 14 days of life. Subsequently, protein levels of the 50 mg/kg offspring increased rapidly so that there were no differences between any of the groups at 21 days of age. These findings for developing CNS parallel the delayed rate of somatic growth previously reported from our laboratory and suggest a transitory rather than a permanent effect of THC on both somatic and brain growth. We also found that THC produces a significant dose-related increase in the sex-ratio of live male-to-female offspring, a finding we have reported previously.     

Tissue distribution of 14C- and 35S-captopril in rats after intravenous and oral administration

35S-Captopril (50 mg/kg) administered i.v. to rats resulted in radioactivity being widely distributed into highly vascular tissues and into excretory organs. After oral administration of 14C-captopril (50 mg/kg), radioactivity in most tissues declined at a rate similar to that in blood. Concn. greater than those in blood were found only in kidney, liver and lung. The high concn. of 14C in kidney and liver were due to the excretory role of these organs. The high concn. of 14C in lung may be due to the high binding affinity of captopril to angiotensin-converting enzyme, present in large quantity in lung.     

Elevation of micronuclei frequency in mouse bone marrow treated with various doses of teniposide (VM-26)

The effect of various doses (0-10 mg/kg body wt.) of teniposide (VM-26) was studied on the induction of micronuclei at 12, 24 and 36 h post-treatment. The frequency of micronuclei (MPCE and MNCE) increased in a dose-dependent manner up to a dose of 0.3125 mg/kg VM-26, where a peak frequency of micronuclei was observed. A further increase in the drug dose resulted in the reduction in micronuclei frequency in comparison with 0.3125 mg/kg drug dose reaching a nadir at 10 mg/kg. However, it was significantly higher than DDW (double distilled water) treated controls. The pattern of micronuclei induction was similar for all the post-treatment time periods. The frequency of micronuclei also increased with scoring time and the highest frequency of micronuclei was observed at 24 h post-treatment, which declined thereafter without restoration to DDW treated control level. Conversely, the PCE/NCE ratio registered a dose-dependent decline after treatment of mice with various doses of VM-26. A peak decline was observed at a dose of 0.3125 mg/kg, thereafter the decline became consistently less resulting in an elevation in the PCE/NCE ratio in comparison with 0.3125 mg/kg VM-26.